The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCCand FANCG

Fanconi anemia (FA) is a chromosomal instability syndrome associated with a strong predisposition to cancer, particularly acute myeloid leukemia and s quamous cell carcinoma, At the cellular level, FA is characterized by spont aneous chromosomal breakage and a unique hypersensitivity to DNA cross-link ing agents. Complementation analysis has indicated that at least seven dist inct genes are involved in the pathogenesis of FA, Despite the identificati on of four of these genes (FANCA, FANCC, FANCF and FANCG), the nature of th e 'FA pathway' has remained enigmatic, as the FA proteins lack sequence hom ologies or motifs that could point to a molecular function. To further defi ne this pathway, we studied the subcellular localizations and mutual intera ctions of the FA proteins, including the recently identified FANCF protein, in human lymphoblasts, FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG. These interactions were detected in wild-type and FA-D lymphoblasts, but not in lymphoblasts of other FA co mplementation groups, This implies that each of the FA proteins, except FAN CD, is required for these complexes to form. Similarly, we show that the in teraction between FANCA and FANCC is restricted to wild-type and FA-D cells . Furthermore, we document the subcellular localization of FANCA and the FA NCA/FANCG complex in all FA complementation groups, Our results, along with published data, culminate in a model in which a multiprotein FA complex se rves a nuclear function to maintain genomic integrity.